The goal of this proposal is to investigate the function of mammalian Sim1 and Sim2 genes using transgenic mouse models. Sim1 and Sim2 are homologs of the Drosophila sim (single-minded) gene. In the fly, sim plays essential roles in the development of the central nervous system. Preliminary studies of the mouse Sim genes strongly suggest evolutionarily conserved functions. The SIM proteins contain conserved sequence motif termed the "PAS" domain which is shared by several environmental sensor proteins such as the Dioxin receptor, the Hypoxia Inducible Factor, the Drosophila circadian rhythm regulator Period, and the Bacillus subtilis sporulation regulator Kin A. This information strongly indicates that SIMs may also respond to specific environmental signals via their PAS domains. This proposal includes the following aims: 1) documenting the expression patterns of Sim1 and Sim2 in detail; 2) establishing mouse models lacking Sim1 and Sim2 gene function by homologous recombination and characterizing the mutant phenotype in order to assess the normal function of these genes; 3). establishing mouse models that overexpress Sim2 to assess the aberrant function of Sim2 due to elevated dosage; and 4). identifying possible small molecule ligands that modulate t he function of Sim1 and Sim2. Importantly, the mouse Sim2 gene is located in the syntenic human Down Syndrome (DS) critical region. Generation of mouse models with overexpressed Sim2 will directly test its involvement in DS. Furthermore, mutant mice lacking Sim1 display neurological disorders that may relate to multiple sclerosis. Exploration and identification of possible small ligands that regulate Sim1 and Sim2 function will be the first step towards developing methods to alter their gene activities in viv The long term goal of this laboratory is to establish mouse models for related human diseases or disabilities that arise either from genetic defects or fetal exposure to exogenous chemicals or stress. Generation of sophisticated mouse models with modern molecular technology will facilitate our understanding of the causes of many human diseases and disabilities, and the development of methods for their prevention, treatment and cure.